Same dose of Japanese cedar pollen sublingual immunotherapy tablets is optimal for allergic rhinitis caused by either Japanese cedar or Japanese cypress pollen
Authors: Minoru Gotoh, Tomoya Kurokawa, Syuji Yonekura, Mitsuhiro Okano, Yuriko Maekawa, Yoshitaka Okamoto, Kimihiro Okubo
Journal: Allergy (2022)

Japanese cedar (JC) pollinosis is the most prevalent and important tree pollen allergy in Japan,1, 2 and about 70% of JC pollinosis patients also have a symptomatic allergy to Japanese cypress (JCY) pollen.1 Consequently, combined JC/JCY pollinosis sufferers experience severe symptoms during the JC (February to April) and JCY (April to May) pollen dispersal seasons. JC and JCY are homologous members of the Cupressaceae tree family.3 Cry j 1 and Cry j 2, the major allergens in JC pollen, have about 80% amino acid sequence homology to Cha o 1 and Cha o 2, the major JCY pollen allergens.4 Thus, there has been increasing interest in recent years in the clinical relevance of the potential antigenic similarity between JC and JCY allergens.4 JC pollen sublingual immunotherapy (SLIT) tablets containing 5000 Japanese allergy units (JAU) of the major JC allergens, including Cry j 1 and Cry j 2, are approved for SLIT for JC pollinosis in Japan. We have previously reported that JC pollen SLIT tablets also suppress allergic symptoms caused by JCY pollen5; however, whether the optimal dosage of JC pollen SLIT tablets for the treatment of JC pollinosis is also optimal for JCY allergic rhinitis has not been established. To address this question, we re-analyzed data from the first season of the 206-2-1 clinical study (JapicCTI No. 142579), a randomized, double-blind, placebo-controlled phase II/III trial of JC pollen SLIT tablets in subjects with JC pollinosis, approximately 80% of whom were also sensitive to JCY pollen (Table S1).6 A total of 1042 patients with JC pollinosis (aged 5–64 years) were randomized into four equal groups to receive daily treatment with placebo or 2000, 5000, or 10,000 JAU JC pollen SLIT tablets (Figure S1).6 The data for each group were re-analyzed to determine the total nasal symptom and medication score (TNSMS) during the peak JCY pollen dispersal period. The daily average TNSMS (Figure 1A) and the mean TNSMS (Figure 1B) in the groups receiving SLIT were consistently lower than those in the placebo group. The absolute and relative differences between the adjusted mean TNSMS for each SLIT group vs the placebo group during the peak JCY pollen dispersal period were: 1.39 and 20.5%, respectively, for the 2000 JAU group; 2.23 and 33.0%, respectively, for the 5000 JAU group; and 2.16 and 31.9%, respectively, for the 10,000 JAU group (all p < 0.001, Table 1A). The least squares mean TNSMS was significantly lower in the 5000 JAU group than in the 2000 JAU group but did not differ significantly between the 5000 JAU and 10,000 JAU groups. The dose–response relationship based on contrast in a linear model with the full analysis set showed that 5000 JAU was the optimal dose with the greatest contrast (F value = 63.40) for alleviation of allergic rhinitis symptoms to not only JC pollen but also JCY pollen (Table 1B). This result is similar to the findings of a previous study investigating the optimal dose of JC pollen SLIT tablets for JC pollinosis during the peak symptom period (20.9%, 31.5%, and 30.9% symptom reduction vs placebo with 2000, 5000, and 10,000 JAU, respectively; all p < 0.001).6 1.39 (0.77 to 2.01) 20.5% (11.8% to 28.4%) 2.23 (1.62 to 2.85) 33.0% (24.9% to 40.4%) 0.85 (0.23 to 1.47) 15.7% (4.5% to 25.8%) 2.16 (1.54 to 2.79) 31.9% (23.6% to 39.5%) 0.77 (0.14 to 1.40) 14.3% (2.8% to 24.7%) −0.07 (−0.70 to 0.55) −1.6% (−16.5% to 11.4%) 1.99 (0.70 to 3.29) 29.9% (11.7% to 45.6%) 2.08 (0.81 to 3.35) 31.2% (13.5% to 46.4%) 0.08 (−1.20 to 1.37) 1.8% (−30.1% to 25.8%) 1.52 (0.22 to 2.82) 22.7% (3.7% to 38.9%) −0.48 (−1.79 to 0.84) −10.2% (−45.1% to 15.7%) −0.56 (−1.86 to 0.73) −12.2% (−47.3% to 14.0%) 1.21 (0.51 to 1.92) 17.8% (7.8% to 26.9%) 2.28 (1.58 to 2.99) 33.5% (24.3% to 42.0%) 1.07 (0.36 to 1.78) 19.1% (6.8% to 30.0%) 2.35 (1.63 to 3.06) 34.5% (25.2% to 43.1%) 1.14 (0.42 to 1.85) 20.3% (8.0% to 31.3%) 0.07 (−0.65 to 0.78) 1.5% (−15.5% to 16.1%) 0.78 (0.38 to 1.19) 15.9% (8.1% to 23.1%) 1.18 (0.78 to 1.58) 23.9% (16.5% to 30.8%) 0.40 (0.00 to 0.80) 9.6% (−0.1% to 18.4%) 1.21 (0.81 to 1.61) 24.4% (16.9% to 31.4%) 0.42 (0.02 to 0.83) 10.2% (0.4% to 19.0%) 0.02 (−0.38 to 0.43) 0.7% (−10.6% to 10.8%) 0.56 (0.11 to 1.01) 13.5% (2.8% to 23.2%) 1.12 (0.67 to 1.57) 26.9% (16.9% to 36.0%) 0.56 (0.10 to 1.01) 15.5% (3.1% to 26.6%) 0.97 (0.51 to 1.43) 23.3% (13.0% to 32.7%) 0.41 (−0.05 to 0.87) 11.4% (−1.5% to 22.8%) −0.15 (−0.61 to 0.31) −4.9% (−21.6% to 9.5%) 0.68 (0.28 to 1.08) 14.8% (6.5% to 22.6%) 1.15 (0.75 to 1.54) 24.9% (17.1% to 32.3%) 0.46 (0.07 to 0.86) 11.9% (1.8% to 21.0%) 1.09 (0.70 to 1.49) 23.8% (15.8% to 31.3%) 0.41 (0.01 to 0.81) 10.6% (0.3% to 19.9%) −0.05 (−0.45 to 0.53) −1.5% (−13.8% to 9.6%) Characterization of allergic rhinitis caused solely by JCY pollen has been difficult in Japan, for two reasons: first, JCY-monosensitized patients have not been reported to date and are very rare,7 and second, the JC pollen dispersal season precedes, but overlaps with, the JCY pollen dispersal season.8 Thus, a dose–response study of JC pollen SLIT tablets in patients sensitized to JCY alone is not feasible. Nevertheless, upon further stratification of the re-analysis data by sensitization status of the homologous pollens, we found that the optimal dose of JC pollen SLIT tablets was 2000 JAU for JC-monosensitized patients (JCY-specific IgE <0.7 UA/ml) and 5000 JAU for patients co-sensitized to JC and JCY (JCY-specific IgE ≥0.7 UA/ml). Moreover, the optimal dose was 5000 JAU for each homologous pollen dispersal period separately as well as the entire overlapping period (Table 1). Considering that >70% of Japanese patients with JC pollinosis are also JCY pollen-sensitized in the clinical setting, these data suggest that the preferred clinical dose would be 5000 JAU for patients sensitized to one or both of these homologous Cupressaceae allergens. Currently, there are no established methods for the measurement of JCY-specific IgG4 or IgE-blocking factor; thus, we cannot show these immunological data. Previous report has shown that allergen-specific IgE and IgG4 of the homologous birch group were altered in a similar manner after treatment of patients to SQ tree SLIT tablets.9 Based on this observation and the demonstration of specific IgE cross-reactivity between JC and JCY pollens from inhibition and absorption tests using sera positive for JCY pollen,7 we confirmed changes in JC-specific IgG4 as a surrogate marker of JCY-specific IgG4. The degree of increase in JC-specific IgG4 was clearly lower at 2000 JAU, but higher at 5000 and 10,000 JAU, with 10,000 JAU being higher than 5000 JAU (data not shown). The 10,000 JAU may show a more favorable immunological response than 5000 JAU, even with a clinically relevant effect of a similar efficacious range when administered over a longer period of time. Nevertheless, treatment with JC pollen SLIT tablets at 5000 JAU for 3 years has demonstrated both long-term efficacy and disease-modifying effects,10 providing clinical support for 5000 JAU as the optimal dose. Ellis et al.,11 using an environmental exposure chamber (EEC), found that administration of Timothy grass SLIT tablets had no effect on symptoms caused by non-homologous birch pollen. In contrast, Couroux et al.,12 also using an EEC, found that administration of SQ tree SLIT tablets reduced allergic rhinoconjunctivitis symptoms caused by homologous birch or oak pollen, with an optimal dose of 12 DU. Thus, the clinical and immunological findings in these studies suggested that SQ tree SLIT tablets could potentially be used to treat allergies to all species within the homologous birch group at the current dose of 12 DU.12 Our results are consistent with this notion of therapeutic cross-reactivity of SLIT between homologous tree allergens and provide support in this context for the treatment of allergies to the Cupressaceae group members JC and JCY, which were assigned by Lorenz et al.3 as identical homologs based on a high degree of amino acid sequence identities of the major allergens and IgE cross-reactivity. Along these lines, a recent study of JC pollinosis patients using an EEC found not only a correlation between JC- and JCY-specific IgE levels at baseline but also in the severity of nasal symptoms induced by JC and JCY pollen exposure,8 suggesting that homology between JC and JCY major allergens has important clinical implications.8 In addition, patients with JC pollinosis exhibited positive for specific IgE to pollens of Cupressaceae group including JC and JCY at baseline and similar increases in specific IgE to the other Cupressaceae family species after administration of JC pollen SLIT tablets.13 Collectively, these data add support for the clinical relevance of cross-reactivity of immune responses to JC and JCY pollen in patients treated with JC pollen SLIT tablets. Taking into consideration the factors mentioned above, our post hoc analysis and conclusion that the dose of 5000 JAU JC pollen SLIT tablets is optimal for the treatment of both JC and JCY pollinosis supports the potential utility of this approach for treating patients with homologous Cupressaceae pollen allergies. MG, SY, KO, and YO conducted the study and were responsible for data collection and interpretation. MO and TK contributed to the study concept. YM wrote the manuscript. All authors were involved in manuscript review and approved the final content. We thank all involved investigators and staff for the work performed in support of this trial. We also thank Anne M. O'Rourke, PhD from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. Editing assistance was funded by Torii Pharmaceutical Co., Ltd, Tokyo, Japan. This trial was funded by Torii Pharmaceutical Co., Ltd., Tokyo, Japan. MG received consulting fees from Torii and honoraria from Torii, Taiho, Hisamitsu, Meiji Seika Pharma, and Novartis. TK received consulting fees and honoraria from Torii. SY received grants from Thermo Fisher Diagnostic, Japan, and Kyowa Kirin, Japan; consulting fees from Torii; and honoraria from Torii, Novartis Pharma, Sanofi, Kyorin, Mitsubishi Tanabe, Hisamitsu, Taiho, and Meiji Seika Pharma. MO received consulting fees from Torii and honoraria from Torii, Mitsubishi Tanabe, Taiho, Sanofi, and Novartis. YO received consulting fees from Torii and honoraria from Torii, Mitsubishi Tanabe, Taiho, Shionogi, Novartis Pharma, Kirin, and Kyorin. KO received consulting fees and honoraria from Torii. YM is employed by Torii. Appendix S1 Supplementary text online repository Figure S1 Trial design and participant disposition. Reasons for screening failure and withdrawal during the dose-finding period have been published previously.E1 "Other" reasons for withdrawal included "lack of efficacy," "pregnancy," "moved from the trial area," and "lost to follow-up". N, number of participants; AA, Active-to-active (5000 JAU re-randomized to receive 5000 JAU); AP, active-to placebo (5000 JAU re-randomized to receive placebo); JAU, Japanese allergy unit; PA, placebo re-randomized to receive 5000 JAU; PP, placebo re-randomized to receive placebo. Table S1 Baseline clinicopathological characteristics of patients in the dose-finding period Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.